Cohen Syndrome With Complex Medical Complications: A Case Report

Cohen syndrome (CS) is a rare autosomal recessive disorder marked by developmental delays, distinct facial features, and a variety of systemic manifestations. We present a case of a 28-year-old male previously misdiagnosed with Prader-Willi syndrome who exhibited recurrent generalized weakness, fever, fatigue, and significant hemoglobin drops requiring multiple blood transfusions due to thalassemia major. The patient displayed characteristic CS features, including developmental delays, distinct facial characteristics, morbid obesity, and heterochromia iridis. Severe gastrointestinal bleeding led to a diagnosis of ulcerative colitis (UC) via colonoscopy. Management included blood transfusions, hydrocortisone, mesalamine, and azathioprine, resulting in stabilized UC and improved overall health. CS presents with a spectrum of clinical features that overlap with other syndromic conditions, necessitating careful differential diagnosis. Early diagnosis and supportive care significantly improve quality of life and help manage complications effectively.


Introduction
Cohen syndrome (CS), an autosomal recessive syndrome first reported in 1973 by Cohen et al., is characterized by developmental delay, distinctive facial features, and a range of systemic manifestations.These include ocular issues such as constricted visual fields and night blindness, hematologic abnormalities like leukopenia, musculoskeletal problems such as ligamentous laxity and hypermobility, and neurological signs such as brisk tendon reflexes and muscular hypotonia.Gastrointestinal challenges, cardiovascular complications, including decreased left ventricular function and valvular defects, and dental issues like prominent upper incisors and alveolar bone loss are also common.CS is primarily caused by mutations in the vacuolar protein sorting 13 homolog B (VPS13B) gene, which encodes a protein involved in intracellular transport and membrane trafficking.These mutations disrupt cellular processes, leading to the characteristic features of CS [1][2][3].
In this study, we present a patient with typical characteristics of CS and many complex medical complications and surgical interventions.Additionally, the patient complained of lower gastrointestinal bleeding with recurrent episodes of anemia despite receiving recurrent blood transfusions.The purpose of this report is to draw attention to such uncommon complications of CS.

Case Presentation
A 28-year-old male patient with CS, previously misdiagnosed with Prader-Willi syndrome, presented with a complex medical history, including thalassemia major and hypothyroidism.He arrived at our hospital experiencing recurrent episodes of generalized weakness, fever, fatigue, and a significant drop in hemoglobin levels, necessitating multiple hospitalizations and blood transfusions due to his thalassemia major.During this visit, he reported lower quadrant abdominal pain and a change in stool color.
In the ER, thorough investigations were conducted, including laboratory tests that revealed a hemoglobin level of 8 g/dL (Table 1), warranting admission for a blood transfusion.Upon admission, the physical examination revealed features consistent with CS, such as developmental delays in motor skills and speech, intellectual disability, distinct facial characteristics like a prominent nose, dental eruptions, heterochromia iridis, and anisomelia (leg length discrepancy) (Figure 1).Additionally, he presented with morbid obesity and tenderness in the lower quadrant of the abdomen, without anal fissures or hemorrhoids, and no active rectal bleeding at the time of assessment.However, two hours later, he began to exhibit symptoms of severe gastrointestinal bleeding, presenting with recurrent episodes of blood per rectum.It is worth noting that genetic testing confirmed the diagnosis of Cohen syndrome, identifying mutations in the VPS13B gene.Blood transfusions continue to effectively manage his thalassemia major, maintaining hemoglobin levels and preventing severe anemia.Iron chelation therapy, initiated to address iron overload from repeated transfusions, helps preserve liver and cardiac function.The patient follows a protocol for periodic transfusions and chelation therapy, with close monitoring to prevent transfusion-related complications.
In the long term, the patient benefits from a stable, multidisciplinary care plan for CS.Genetic counseling provides valuable insights and support to the patient and his family, helping them understand the condition and manage expectations.Thyroid hormone replacement therapy is regularly adjusted based on thyroid function tests, ensuring normal thyroid hormone levels and preventing symptoms of hypothyroidism.
Nutritional support and obesity management lead to gradual weight loss and improved overall health.
Through dietary counseling and a tailored physical therapy regimen, the patient develops healthier eating habits and enhances his physical fitness.Psychological support and special education resources help address intellectual disability and developmental delays, improving his quality of life and providing effective coping strategies.
Regular monitoring identifies potential complications early, allowing for prompt intervention.The patient is closely observed for infections due to immunosuppressive therapy, cardiovascular health issues related to obesity and chronic illness, and liver dysfunction from iron overload.Periodic assessments ensure that any arising complications are managed effectively, maintaining his overall health.
With a structured follow-up schedule, the patient experiences fewer hospitalizations and better management of his chronic conditions.Weekly monitoring of hemoglobin levels and vital signs, monthly comprehensive blood work, and quarterly reviews of his treatment plan provide consistent and proactive care.Annual evaluations, including genetic counseling follow-up, bone density assessments, and full endocrinological and hematological reviews, offer comprehensive insights into his health, allowing for necessary adjustments to his care plan.

Discussion
CS is a complex genetic disorder that affects multiple body systems.Specifically, this rare condition manifests with a spectrum of clinical features, including intellectual disability, characteristic facial appearance, and various physical abnormalities.Consequently, the differential diagnosis includes several other syndromic conditions due to their diverse manifestations.For example, Bardet-Biedl syndrome shares features such as obesity, retinal dystrophy, and developmental delays but can be distinguished by polydactyly and renal anomalies.Similarly, Prader-Willi syndrome is characterized by hypotonia, obesity, and developmental delays, with distinct features such as hyperphagia and specific facial dysmorphisms.Likewise, Angelman syndrome presents with intellectual disability and a happy demeanor, similar to CS, but includes ataxia and seizures.Additionally, Smith-Lemli-Opitz syndrome involves developmental delay, facial dysmorphisms, and growth retardation and is distinguishable by abnormalities in cholesterol metabolism.Furthermore, Alström syndrome features obesity and retinal dystrophy but differs from progressive hearing loss and cardiomyopathy [4][5][6][7][8].
UC needs to be differentiated from other inflammatory and non-inflammatory conditions of the gastrointestinal tract.Crohn's disease can affect any part of the GI tract, presents with transmural inflammation, and commonly involves skip lesions.Infectious colitis is caused by bacterial, viral, or parasitic infections, usually identified through stool cultures.Irritable bowel syndrome is characterized by abdominal pain and altered bowel habits without the inflammatory markers seen in UC.Ischemic colitis typically occurs in older adults, is associated with sudden-onset abdominal pain, and is often linked to vascular diseases.Diverticulitis involves inflammation of the diverticula in the colon, presenting with localized pain, often in the lower left quadrant [9][10][11][12][13].
CS presents a variety of clinical features.Characteristic facial dysmorphisms include a high nasal bridge, a long philtrum, down-slanting palpebral fissures, and micrognathia (a small jaw).Motor and intellectual development are typically delayed.Central obesity often becomes noticeable during childhood.Progressive retinal dystrophy and myopia are common, leading to vision impairment.Intermittent neutropenia increases susceptibility to infections, and low muscle tone along with hypermobile joints are frequently observed [4,5,14].
The primary diagnosis of CS is going through clinical evaluation, with genetic testing used to identify mutations in the VPS13B gene.Specifically, the clinical diagnosis is based on characteristic facial features, developmental delays, retinal dystrophy, neutropenia, and truncal obesity.Identifying VPS13B mutations confirms the diagnosis.Consequently, the prognosis of CS varies depending on the severity of symptoms (Tables 2-3).While individuals may have a relatively normal lifespan, they often face challenges related to intellectual disability, visual impairment, and recurrent infections due to neutropenia.Therefore, early diagnosis and supportive care can significantly improve the quality of life and help manage complications effectively [15,16].

Conclusions
We describe the complexity and multifaceted nature of Cohen syndrome in this case, emphasizing the need for accurate differential diagnosis and a comprehensive, multidisciplinary approach to management.The overlap of clinical features with other syndromic conditions underscores the importance of thorough clinical evaluation and genetic testing for an accurate diagnosis.Early recognition and targeted interventions, including the management of gastrointestinal complications and chronic conditions like thalassemia major, can significantly enhance patient outcomes.Continued follow-up and supportive care are crucial in improving the quality of life and managing the diverse manifestations of Cohen syndrome.

FIGURE 1 :
FIGURE 1: Illustrates several notable clinical findings.Image 1 reveals heterochromia iridis, characterized by different iris colors in the same individual.Image 2 depicts morbid central obesity, a severe form of obesity with significant health implications.Image 3 demonstrates anisomelia, indicating a discrepancy in leg length.Finally, Image 4 showcases dental eruptions.

TABLE 1 : Illustrates comparative laboratory values on admission day and discharge day.
Hb: hemoglobin, Hct: hematocrit, RBC: red blood cell, MCV: mean corpuscular volume, WBC: white blood cell, TIBC: total iron binding capacity, CRP: Creactive protein, ESR: erythrocyte sedimentation rate, ALT: alanine aminotransferase, AST: aspartate aminotransferase, ALP: alkaline phosphatase, BUN: blood urea nitrogen, TSH: thyroid-stimulating hormone, FT4: free thyroxine, PT: prothrombin time, PTT: partial thromboplastin time, INR: international normalized ratio.Further investigations, including a colonoscopy and biopsy due to suspected colonic involvement, revealed mucosal inflammation in the colon, confirming the diagnosis of ulcerative colitis (UC).The patient's management included regular blood transfusions, the administration of intravenous fluids and medications such as hydrocortisone, and close monitoring of vital signs and hemoglobin levels.Following initial treatment, the patient's UC begins to stabilize under the administration of intravenous hydrocortisone.The acute gastrointestinal bleeding episodes subside, allowing for a transition to oral steroids.With the addition of aminosalicylates like mesalamine and immunomodulators such as azathioprine, the inflammation in his colon is brought under long-term control.Regular follow-up 2024 Milhem et al.Cureus 16(8): e66033.DOI 10.7759/cureus.66033colonoscopies reveal gradual mucosal healing, and the frequency and severity of gastrointestinal bleeding decrease significantly.